The longitudinal history of medicines innovation: Part two

As we move forward in public discussions on pharmaceutical innovation and its value to patients and society, it is helpful to ground conversations in a solid understanding of how medicines development occurs.

The second of a two-part article, CRA’s Life Sciences Practice team, along with experts at Johnson & Johnson, recently conducted a landscape review of how complex pharmaceutical innovation happens in practice, leveraging three therapy area case studies: HIV/AIDS, multiple sclerosis, and multiple myeloma.

The critical role of complementary technological advances

Beyond advances in the understanding of diseases and real-world data of new treatments, wider technological advances have been critical to the development of novel medicines.

To support advancements in R&D for HIV/AIDS treatments, it was critical for researchers to establish the relationship among viral load and CD4+ T-cell count with the ability to measure these through CD4 counting (established in 1995) and quantitative HIV RNA testing (established in 1996). These technological advances enabled researchers to use lab test results to assess the efficacy of investigational antiretroviral agents, while community treatment activism led to the adoption of these indicators as surrogate endpoints in clinical trials, shortening the length of trials from several years to about six months and increasing the capacity to conduct clinical trials.^1,2 Another technological advancement in the field was the ability to chemically synthesise proteins in the lab to develop protease inhibitors.

In the case of MS, advances in MRI techniques in the 1970s and 1980s enabled the visualisation of the central nervous system in a way that could quantify lesions. Scientists also developed techniques for the synthesis of recombinant interferons, which enabled the biotech company Cetus and others to ultimately overcome limits to the available quantities of natural interferons and allow clinical development at scale.³ Similarly, for MM, technological progress in the production of mAbs paved the way for early commercialisation and wide-scale production of mAbs for patient use and the development of this class of treatment.

Failure as table-stakes for long-term success

Successful innovation has typically resulted from persistence and learning from failures, both within the relevant therapy area, and even through the failure of compounds first developed for other indications.

This was particularly true for the earliest HIV/AIDS treatments, developed during a time when many virologists were pessimistic that viral suppression could be achieved without harming normal cells, given HIV’s ability to integrate itself in the host DNA. They believed that vaccine development would be more successful.⁴ Azidothymidine (AZT) was originally researched as a potential cancer drug candidate by NCI researchers in 1964, but was shelved due to lack of efficacy.⁵ Decades later, AZT eventually gained approval as the first anti-HIV treatment. Several companies also worked to develop novel classes of medicines for HIV, with many failures. In fact, for each successful drug approved for HIV/AIDS, there have been around 1,800 compounds tested for inhibitory activity.⁶

The progressive form of MS has been a consistently risky target indication, due to limited understanding of the pathophysiology of disease progression. From 2015-2020, clinical trials failed for compounds with various mechanisms of action, including B-cell targeting agents like rituximab, T-cell targeting therapies like imilecleucel‑T, and compounds that block or sequester lymphocyte trafficking, such as fingolimod and natalizumab.⁷ Nevertheless, such failures serve as important contributions to the understanding of MS’s pathophysiology and can ultimately benefit the design of future studies.

The history for MM is also a mix of successes and failures, with second generation treatment approaches improving on first-to-market products. As single agents, histone deacetylases (HDAC) inhibitors do not have significant activity in MM and are used in combinations to work synergistically, particularly with proteasome inhibitors. While Novartis gained approval for panobinostat in refractory MM, MSD discontinued its pursuit of the MM indication for its first-in-class HDAC inhibitor.^8,9,10 Biopharmaceutical companies ultimately pursued the development of safe and effective nuclear export inhibitors and BCL-2 inhibitors, despite the first-generation therapies demonstrating poor efficacy and dose-limiting toxicities.

Growing benefits to patients

For all three therapy areas, there have been immense improvements in the treatments that are available to patients, treatments that taken together, over a few decades, have done much to improve patient outcomes and address unmet need through both incremental and breakthrough improvements.

In the case of HIV/AIDS, since the global peak in 2004, AIDS-related deaths have decreased by 64%,¹¹ and the number of new infections has steadily decreased as new antiretrovirals have emerged.¹² Today, a person living with well managed HIV/AIDS can expect to live into old age.¹³ With the appropriate access to care and antiretrovirals, HIV infection has become a chronic condition. Work on vaccines and new therapies continues.

While there is still no cure for MS, a steady increase in the number and efficacy of treatments has transformed MS into a more manageable condition. Progress has been made over time with improved patient short- and long-term outcomes, such as long-term brain preservation through structural analysis of brain volume loss, fewer relapses through annualised relapse rate (ARR) clinical trial endpoints, and very importantly through fewer new MRI lesions.^14,15

With each new class of MM treatments from the early 2000s to today, there have been cumulative improvements in patient outcomes and median overall survival from only three to four years at diagnosis to the current estimated median of eight to 10 years.¹⁶ The response of patients today to triplet drug regimens is a far cry from that observed during the time of first-generation treatments in the 1970s and 1980s.

Conclusion

Overall, our case study research demonstrates that innovation has been the result of collaborative and complementary contributions by biopharmaceutical companies, academic researchers, and public organisations. Such synergistic efforts lead to improved therapies over time, as we learn more about diseases from both basic research and lived experience with approved medicines. Success depends on a high level of clinical and competitive risk-taking to drive innovation forwards and to ensure that patients benefit from technological advances and new treatment options. There remains much more to do in each therapy area, however, the overall story so far is overwhelmingly one of progress.

About the authors

Tim Wilsdon is VP in the life sciences practice at CRA and leads the policy sector in the global life sciences practice. He is a regular contributor to international conferences on health policy and has also acted as an expert in international arbitrations involving multinational pharmaceutical companies. He was responsible for leading an assignment for the European Commission, determining whether there was a global crisis in innovation and the risks of importation.

Clara Zacharko is a consulting associate in the life sciences practice at CRA. She focuses on health policy consulting and has experience in analysing and understanding the impacts of changes in the policy landscape on pharmaceutical innovation in North American and EU markets.

Hugh Nicholl is an associate in the life sciences practice at CRA. He works across strategy and policy consulting, with a focus on the health policy landscape and market access for pharmaceuticals in the EU.

The authors wish to acknowledge the contributions of Dr Reina Benabou, Dr Richard E. Nettles, Dr J. Blake Bartlett, and Danielle Rollmann from Janssen, and Adrian Griffin from Johnson & Johnson to this article. The research for the underlying case studies was funded by The Janssen Pharmaceutical Companies of Johnson & Johnson.

The views expressed herein are the authors’ and not those of Charles River Associates (CRA) or any of the organisations with which the authors are affiliated.